OBJECTIVE—To determine the contribution of maternal glucose and lipids to intrauterine metabolic environment and fetal growth in pregnancies with gestational diabetes mellitus (GDM). RESEARCH DESIGN AND METHODS—In 150 pregnancies, serum triglycerides (TGs), cholesterol, free fatty acids (FFAs), glycerol, insulin, and glucose were determined in maternal serum and cord blood during the 3rd trimester. Maternal glucose values came from oral glucose tolerance testing and glucose profiles. Measurements of fetal abdominal circumference (AC) were performed simultaneously with maternal blood sampling and birth weight, and BMI and neonatal fat mass were obtained following delivery. RESULTS—Maternal TGs and FFAs correlated with fetal AC size (at 28 weeks: triglycerides, P = 0.001; FFAs, P = 0.02), and at delivery they correlated with all neonatal anthropometric measures (FFA: birth weight, P = 0.002; BMI, P = 0.001; fat mass, P = 0.01). After adjustment for confounding variables, maternal FFAs and TGs at delivery remained the only parameters independently related to newborns large for gestational age (LGA) (P = 0.008 and P = 0.04, respectively). Maternal FFA levels were higher in mothers with LGA newborns than in those with appropriate for gestational age (AGA) newborns (362.8 ± 101.7 vs. 252.4 ± 10.1, P = 0.002). Maternal levels of TGs, FFAs, and glycerol at delivery correlated with those in cord blood (P = 0.003, P = 0.004, and P = 0.005, respectively). Fetal triglyceride and cholesterol levels were negatively correlated with newborn birth weight (P = 0.001), BMI (P = 0.004), and fat mass (P = 0.001). TGs were significantly higher in small for gestational age (SGA) newborns compared with AGA or LGA newborns, while insulin-to-glucose ratio and FFAs were the highest in LGA newborns. CONCLUSIONS—In well-controlled GDM pregnancies, maternal lipids are strong predictors for fetal lipids and fetal growth. Infants with abnormal growth seem to be exposed to a distinct intrauterine environment compared with those with appropriate growth.

Insulin resistance plays a role in the pathogenesis of diabetes, including gestational diabetes. The glucose clamp is considered the gold standard for determining in vivo insulin sensitivity, both in human and in animal models. However, the clamp is laborious, time consuming and, in animals, requires anesthesia and collection of multiple blood samples. In human studies, a number of simple indexes, derived from fasting glucose and insulin levels, have been obtained and validated against the glucose clamp. However, these indexes have not been validated in rats and their accuracy in predicting altered insulin sensitivity remains to be established. In the present study, we have evaluated whether indirect estimates based on fasting glucose and insulin levels are valid predictors of insulin sensitivity in nonpregnant and 20-day-pregnant Wistar and Sprague-Dawley rats. We have analyzed the homeostasis model assessment of insulin resistance (HOMA-IR), the quantitative insulin sensitivity check index (QUICKI), and the fasting glucose-to-insulin ratio (FGIR) by comparing them with the insulin sensitivity (SI_Clamp) values obtained during the hyperinsulinemic-isoglycemic clamp. We have performed a calibration analysis to evaluate the ability of these indexes to accurately predict insulin sensitivity as determined by the reference glucose clamp. Finally, to assess the reliability of these indexes for the identification of animals with impaired insulin sensitivity, performance of the indexes was analyzed by receiver operating characteristic (ROC) curves in Wistar and Sprague-Dawley rats. We found that HOMA-IR, QUICKI, and FGIR correlated significantly with SI_Clamp, exhibited good sensitivity and specificity, accurately predicted SI_Clamp, and yielded lower insulin sensitivity in pregnant than in nonpregnant rats. Together, our data demonstrate that these indexes provide an easy and accurate measure of insulin sensitivity during pregnancy in the rat.

During the first two-thirds of gestation, the mother is in an anabolic condition, increasing her fat depots thanks to both hyperphagia and enhanced lipogenesis. During the last third of gestation, the mother switches to a catabolic condition. Glucose is the most abundant nutrient crossing the placenta, which causes maternal hypoglycemia despite an increase in the gluconeogenetic activity. Adipose tissue lipolytic activity becomes enhanced, increasing plasma levels of FFA and glycerol that reach the liver; consequently there is an enhanced production of triglycerides that return to the circulation in the form of very low density lipoproteins (VLDL). Glycerol is also used as a preferential gluconeogenetic substrate, saving other more essential substrates, like amino acids, for the fetus. Under fasting conditions, fatty acids are converted into ketone bodies throughout the β-oxidation pathway, and these compounds easily cross the placental barrier and are metabolized by the fetus. An enhanced liver production of VLDL-triglycerides together with a decrease in adipose tissue lipoprotein lipase (LPL) and an increase in plasma activity of cholesterol ester transfer protein causes both an intense increment in these lipoproteins and a proportional enrichment of triglycerides in both low and high density lipoproteins. Maternal triglycerides do not cross the placenta, but the presence of LPL and other lipases allows their hydrolysis, releasing fatty acids to the fetus. Under fasting conditions, the maternal liver uses circulating triglycerides as ketogenic substrates. Around parturition there is an induction of LPL activity in the mammary glands, driving circulating triglycerides to this organ for milk synthesis, allowing essential fatty acids derived from the mother’s diet to become available to the suckling newborn. European Journal of Clinical Nutrition (2000) 54, Suppl 1, S47–S51

More glucose crosses the placenta than any other substrate, but correlations between its concentration in maternal plasma and fetal growth are not found consistently. The accumulation of maternal fat depots and hyperlipidemia are the two principal changes in lipid metabolism during pregnancy. Although lipids cross the placenta with difficulty, maternal plasma triacylglycerols (TAG) and non-esterified fatty acids (NEFA) correlate with fetal lipids, fetal growth and fat mass under certain conditions. In intrauterine growth restriction, impaired placental transfer of lipophilic compounds (long-chain polyunsaturated fatty acids and lipophilic vitamins) seems to underpin metabolic dysfunction and decreased birth weight. In gestational diabetes mellitus (GDM), maternal TAG and NEFA levels correlate with neonatal anthropometric measures. In GDM, adipocyte fatty acid-binding protein in fetuses correlated with neonatal fat mass; changes in maternal or cord blood leptin, retinol binding protein 4 and adiponectin concentrations have been related to neonatal fat mass or birth weight, although their importance remains to be investigated. The angiopoietin-like protein 4 (ANGPTL-4) is secreted from adipose tissue, liver and placenta, and irreversibly inhibits lipoprotein lipase (LPL) activity. Maternal plasma ANGPTL-4 is decreased in GDM, and it has been proposed to be responsible for an increase in placental LPL activity, which would facilitate a greater fatty acid placental transfer, contributing to the higher fetal fat accumulation. Thus, while evidence suggesting major involvement of maternal lipid metabolism in fetal adiposity and growth exists, the precise mechanisms remain to be elucidated.